This is a resubmission of a new program project application directed by the Chief of Neurology at Massachusetts General Hospital, Dr. Anne B. Young, who was Director of the Michigan Alzheimer's Disease Research Center before moving to MGH in August, 1991. Prior to Dr. Young's arrival, the investigators were each examining independent aspects of neurodegeneration and Alzheimer's disease (AD) and in this new effort, they will combine forces to explore the excitotoxic and metabolic cascade that predisposes the brain to aging and AD. Five projects and two cores are proposed. Project 1 will examine the hypothesis that cells that are vulnerable in AD contain a high density of NMDA and metabotropic receptors, protein kinases and amyloid precursor protein (APP) or amyloid precursor-like protein (APLP) and a low density of GLuR2. receptors. Project 2 will examine the hypotheses that neurons in "at-risk" regions develop abnormal tau proteins early in the disease, that vulnerable neurons contain high densities of MAP kinases, and that APP and APLP are differentially expressed near sine plaques. Project will investigate the hypotheses that progressive impairment of mitochondrial energy metabolism develops in normal aging, that defective energy metabolism occurs in AD brain and peripheral tissues and that these events predispose to increased cortical and hippocampal damage. Project 4 will examine the regulatory characteristics of the APP gene family (APP, APLP1 and APLP2, etc), their promoters, their processing (i.e., splicing, synthesis, degradation) and the hypothesis that APP and APP-like messages are altered in specific brain regions in aging and AD. Project 5 will utilize a model of aging neurons in cell culture to study the effects of excitatory, thermal-, metabolic and age-induced stress on amyloid precursor protein processing. All projects will utilize the administrative and reagent cores and the latter will perform molecular assays common to all projects. The revised program is thus a multidisciplinary effort that includes state-of-the-art molecular, cell culture, neurochemical, electrophysiologic, anatomic and neuropathologic techniques to study the cellular vulnerability in aging and AD.